The role of humoral and neuronal factors in the control of cerebral blood flow and metabolism is controversial. We studied the control of cerebral blood flow and metabolism under normal and stressful conditions. Our initial work was done with the hypercapnic models for stress, but the studies may be extended to other models of stress, e.g., hypoxia, hypoglycemia and withdrawal from chronic alcohol consumption. Our initial observations demonstrated that the adrenal medulla was the source of factors that controlled the response of cerebral blood flow to hypercapnic stress. Further work indicated that one of these factors was a delta- opioid peptide. Also, recent work demonstrated that the response of cerebral blood flow to hypercapnic stress is mediated through the nitric oxide synthesizing system. These studies showed, however, that the pathways involving nitric oxide synthetase that are responsible for the hypercapnic increases in cerebral blood flow and oxygen consumptions do not involve NMDA receptors. Recent studies have shown that at least part of the increase in cerebral blood flow in hypercapnia is coupled to an increase in cerebral oxygen consumption.